Reduction of Endogenous Angiogenesis Inhibitors in Bruch's Membrane of the Submacular Region in Eyes With Age-Related Macular Degeneration

Abstract

Objectives: To determine the relative levels of 3 potent inhibitors of angiogenesis (endostatin, pigment epithelium-derived factor, and thrombospondin 1) in the retinal pigment epithelium-Bruch's membranechoriocapillaris complex in the submacular region in aged control eyes and eyes with age-related macular degeneration (AMD). Methods: Immunohistochemical analysis with antibodies against endostatin, pigment epithelium-derived factor, and thrombospondin 1 was performed on the macular region of aged control donor eyes (n = 8; mean age, 79.8 years) and eyes with AMD (n = 12; mean age, 83.9 years). Three independent masked observers scored the reaction product (scored from 0-7). Mean scores from the control eyes and the eyes with AMD were analyzed using 1-way analysis of variance and unpaired t test. Results: In control eyes, strong immunoreactivity of all 3 inhibitors was observed in the retinal pigment epithelium-Bruch's membrane-choriocapillaris complex. Immunoreactivity for endostatin, pigment epithelium-derived factor, and thrombospondin 1 in Bruch's membrane was significantly lower in eyes with AMD compared with aged control eyes (analysis of variance, P=.003, P =.009, and P Ͻ.001, respectively). In the choriocapillaris, a significant reduction was observed in endostatin (analysis of variance, P = .02) and thrombospondin 1 (analysis of variance, P =.005) in eyes with AMD. Conclusions: These findings suggest that endogenous angiogenesis inhibitors in the retinal pigment epithelium-Bruch's membrane-choriocapillaris complex may provide a biochemical barrier for choroidal neovascular invasion. Clinical Relevance: Decreased levels of angiogenic inhibitors at the retinal pigment epithelium-Bruch's membrane-choriocapillaris complex in eyes with AMD make Bruch's membrane vulnerable to choroidal neovascularization.

Regulation of Angiogenesis in Choroidal Neovascularization of Age Related Macular Degeneration by Endogenous Angioinhibitors

“…The significance of imbalance in the levels of endogenous angioinhibitors and angioactivators in regulation of vascular homeostasis can be summarized as in Figure 1. This significance was also ascertained by the evaluations showing the correlation between the decrease in specific angioinhibitors and the progression of CNV (Bhutto et al, 2008).…”

“…Addition of PEDF to the cultured HUVECs increased the number of TUNEL positive cells suggesting apoptotic mode of action of PEDF and thus, possibly preventing EC response to ischemia in-vivo (Ho et al, 2007). The levels of PEDF were found to be decreased in Bruch membrane with progression of AMD and concomitant increase in VEGF levels were also identified with decrease in PEDF levels (Bhutto et al, 2008). Different methods of PEDF upregulation have been applied to investigate the effect of PEDF on CNV.…”

“…TSP-1 is secreted by the retinal-pigmented epithelium (RPE) and regulates angiogenesis in normal eye (Miyajima-Uchida et al, 2000). Immunolocalization studies showed decrease in the levels of TSP in the chorio-capillaries and the Bruch membrane of AMD samples (Bhutto et al, 2008). Wispostatin-1 (WISP-1) repeat derived peptide from TSP-1 was shown to inhibit the CNV in LASER induced CNV mice models (Cano Mdel et al, 2009).…”

“…Endostatin is found in normal circulation enabling it to be utilized as an effective angioinhibitor without toxic effects (Fukai et al, 2002). Lower levels of endostatin have been recorded in CNV samples compared to the healthy donor eyes and within the tissues of progressive AMD (Bhutto et al, 2008;Fukai et al, 2002). Deletion of endostatin or collagen type XVIII massively up-regulates LASER induced CNV; where as administration of physiological concentrations of endostatin was able to inhibit such CNV in these mice (Marneros et al, 2007).…”

Degeneração macular relacionada à idade: considerações histopatológicas

“…Tal achado motivou a utilização de drogas antiVEGF na prevenção e tratamento desta doença (9,11) . Os lipídios têm papel fisiopatogênico na DMRI; o acúmulo de lipoproteínas no curso do envelhecimento na MB e a presença de lipídios nas drusas têm contribuição relevante (12,13) .…”